A lack of neutralizing antibodies distinguishes HIV-1 from most other viral pathogens and is responsible to a large degree for the ability of HIV-1 to maintain a persistent infection. A few monoclonal antibodies have been isolated that are broadly neutralizing. We have used X-ray crystallography to investigate the epitopes of broadly neutralizing antibodies and their mechanisms of neutralization. In particular, we have examined CD4-induced (CD4i) antibodies that recognize the coreceptor-binding site, membrane-proximal-binding antibodies like 2F5, CD4-binding-site antibodies like b12, and quaternary specific antibodies like 2909. The b12 analysis lead to the identification of a site of vulnerability to neutralizing antibody on HIV-1, which we are now pursuing as a prime vaccine target.